Reliability, validity, and responsiveness of the Thai version of the Dry Eye-Related Quality-of-Life Score questionnaire

Dry eye disease (DED) is a common and growing eye problem worldwide. Chronic DED symptoms can, subsequently, affect the patients’ quality of life (QOL). This prospective cross-sectional study aimed to assess the reliability, validity, and responsiveness of the Thai version of the Dry Eye-Related Quality-of-Life Score (DEQS-Th) questionnaire and to evaluate its accuracy in DED screening. Psychometric validation was conducted on DED participants. All participants completed the DEQS-Th and other measurements including the Ocular Surface Disease Index (OSDI) and the 5-level EQ-5D (EQ-5D-5L). Internal consistency, concurrent validity, convergent, and discriminant validity were evaluated. The standardized response mean (SRM) was used to evaluate the responsiveness of the DEQS-Th. The optimal cut-off score of DEQS-Th for DED screening was assessed. Among 100 participants with a mean age of 50.9 ± 14.4 years, and 89.0% female, the internal consistency of the DEQS-Th was excellent (Cronbach’s alpha: 0.80–0.92). The test-retest intraclass correlation was 0.82–0.92. It showed concurrent validity with the OSDI (r = 0.694, p < .001) and EQ-5D-5L index scores (r = -0.578, p < .001). DED is suspected if the DEQS-Th score ≥ 18.33 (AUC = 0.897, sensitivity 90.0%, specificity 76.7%) or its Short Form score ≥ 3 (AUC 0.857, sensitivity 93.0%, specificity 63.3%). The SRM of the symptom subscale of DEQS-Th was 0.82, indicating relatively large responsiveness, whereas the impact on daily life subscale and the summary score was small. In conclusion, the DEQS-Th is valid and reliable for evaluating the multifaceted effects of DED on a patient’s QOL. It can be useful for primary assessment and monitoring of DED in routine clinical practice.


Introduction
Dry eye disease (DED) is characterized by a vicious cycle of tear film instability and hyperosmolarity leads to ocular surface inflammation and damage, and neurosensory abnormalities [1]. It is a common eye problem worldwide and one of the frequent causes of patients seeking eye care practitioners [2]. DED prevalence is expected to be increased further because of the a1111111111 a1111111111 a1111111111 a1111111111 a1111111111

Study participants
One hundred participants, diagnosed as DED at the Ophthalmology Clinic, Chiang Mai University Hospital, were recruited between 2018-2019. The eligible criteria included adult subjects aged � 18, voluntary participation, and literate in Thai. The criteria for diagnosis of DED complied with those defined by the DEWS II. Table 1 shows the inclusion and exclusion criteria for participant selection.
All participants underwent complete ophthalmic examination for both eyes including measuring of visual acuity, intraocular pressure, and additional dry eye tests such as corneal fluorescein staining (CFS), TBUT, and basic tear secretion (Schirmer's test). CFS scores were assigned based on a modified van Bijsterveld grading system (the average score was the mean of the sum scores of the 3-area nasal, mid, and temporal cornea ranging from 0 [none] to 3 [maximum]) [20]. TBUT was measured using fluorescein staining without anesthesia. The participant was asked to blink several times. The interval between the last complete blink and the first dry spot on the cornea was measured and the average of three consecutive TBUT was recorded. Schirmer's test was performed with anesthesia. After drying the excess tears, the Schirmer strip was placed at the lateral one-third of the lower fornix for five minutes. The strip was then removed and the wetting length of the filter paper was measured in mm.

Procedure
All DED participants were asked to complete the DEQS-Th questionnaire and additional health-related QOL questionnaires including the OSDI and the 5-level EuroQol-5-Dimensions (EQ-5D-5L).
To evaluate the reproducibility, the DED participants completed the DEQS-TH twice. The re-test was performed two weeks after the first test.
To evaluate the responsiveness or change of the questionnaire regarding the response to treatment, ten patients received diquafosol tetrasodium 3% ophthalmic solution six times/day for treatment of DED. This eye drop is a purinergic P2Y2 receptor agonist on the ocular surface. It stimulates both water and mucin secretion from conjunctival epithelial cells and goblet cells, thereby rehydrating the ocular surface independent of tear secretion from the lacrimal glands [21][22][23]. Participants were asked to complete the DEQS-Th before and at four weeks (± 3 days) after diquafosol treatment. Instruments Dry Eye-related Quality-of-Life Score. The DEQS questionnaire contains 15 questions divided into two subscales: Bothersome Ocular Symptoms (6 questions) and Impact on Daily Life (9 questions). Each question has columns A and B for the frequency and severity, respectively. Response to the frequency portion in column A is based on a 5-point scale ranging from "none of the time" (0) to "all of the time" (4). A frequency score of 1-4 points prompts the respondent to proceed to the severity in column B to answer regarding the degree of severity on a four-point scale. The DEQS score is calculated with the following formula: (sum of the degree scores for all questions answered) x 25/ (total number of questions answered). The score "0" indicates the best possible score (no symptoms) and "100" indicates the worst possible score (maximum symptoms) [14].
Thai version of the Dry Eye-related Quality-of-Life Score. The DEQS-Th was developed from the English version of the DEQS questionnaire [14]. In brief, after permission from the owner of the DEQS (the Asia Dry Eye Society and Santen Pharmaceutical Co., Japan.), the translation and cross-cultural adaptation of the DEQS questionnaire into Thai was conducted according to principles of good practice reported by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) [24]. Language translation and cultural adaptation, then preliminary psychometric validation with 30 normal participants were performed in our previous study [19].
EuroQol-5-Dimensions 5-Level. The EQ-5D, developed by EuroQoL, is composed of five items concerning 'mobility´, 'self-care, 'usual activities´, 'pain/discomfort´, and 'anxiety/ depression [26]. It is a 5-point Likert scale, ranging from 0 (no problem) to 5 (unable/extreme problems). The EQ-5D has two parts, 1) a descriptive system that calculates a five-digit code specifying a specific health state to the index score. The score ranges from 0 to 1, with 0 meaning death and 1 meaning complete health. However, the index score can also have a negative value, meaning worse than dead, 2) and a visual analog scale (EQ-VAS), ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The Thai version EQ-5D-5L and the index score were used in this study [27].

Statistical analysis
The participants' demographic data were descriptively analyzed. The CFS, TBUT, and Schirmer test from the worse eye was used for data analysis. For numerical data, the mean (SD) was used for data with normal distribution, while the median (range) was used for non-normally distributed data. The internal consistency was calculated to evaluate the reliability of the questionnaire; Cronbach's alpha coefficient � 0.7 was considered acceptable. Intraclass correlation coefficient (ICC) was calculated to determine the temporal relationship in test-retest reliability. Concurrent validity was evaluated using Pearson's correlation coefficient to evaluate the correlations between the DEQS-Th scores and other measurements including the OSDI and EQ-5D-5L index scores. Convergent validity is denoted by the level of correlation between constructs and instruments. These relations may be strong or weak correlations depending on the relationship expected between the constructs or instruments compared [28]. We created a correlation matrix between the QOL assessed by the subscale Impact on Daily Life scores of the DEQS-Th and scores from EQ-5D. Correlations would be expected to be high if the similar domain of impact of daily life and EQ-5D were assessed, thereby demonstrating convergent validity.
Discriminative validity was conducted to assess whether a measure can discriminate between the groups [28]. The total scores of DEQS-Th were analyzed to compare normal and clinical samples to indicate its discriminatory ability.
Responsiveness is defined as an ability of a measurement to detect clinically significant changes over time [29]. It was evaluated by comparing the DEQS-Th scores at baseline and follow-up periods after treatment using the standardized response mean (SRM). SRM values of 0.8, 0.5, and 0.2 were considered to be large, moderate, and small, respectively [30].
Floor or ceiling effects indicate the limitation of content validity, and reliability of the questionnaire. Floor or ceiling effects were suggested to be no more than 15% [31]; otherwise, it may affect responsiveness as the participants' changes cannot be assessed [29].
To find the optimal cut-off score of DEQS-Th for suspected DED, the gold standard diagnosis for dry eye was made by using the OSDI score of � 13 and the TBUT of � 5 seconds. The receiver operating characteristic (ROC) curve was generated and the area under the ROC (AUC) was analyzed to determine the accuracy of the DEQS-Th. Sensitivity, specificity, positive predictive value, negative predictive value, and estimated cost were calculated. To simply apply in real-life practice, we also evaluated the Short Form DEQS-Th (SF DEQS-Th) for DED screening by using a sum of frequency scores of subscale Bothersome Ocular Symptoms. Our previous published data from non-DED participants were served as a control in some parts of the analysis [19]. A p-value < 0.05 was used to determine the significant level. SPSS program (version 22.0, SPSS Inc., Chicago, IL, USA) was used for data analysis.

Participants
Among100 DED participants, 89% were females with a mean age of 50.9 ± 14.4 (20-84) years. The participants' demographic data were demonstrated in Table 2. According to the OSDI grading severity, the dry eye symptoms were classified as a mild-to-moderate degree in 30% and a severe degree in 70% of the patients. The mean OSDI score was 46.8 ± 21.4 for all DED participants. No floor or ceiling effects were found in the total scores of the DEQS-Th.

Psychometric analysis
Item analysis. The mean frequency and degree score of each item, as well as the total DEQS-Th score, were significantly higher in DED participants than in non-DED participants indicating discriminant validity (Tables 2 and 3).
Reliability. The results of internal consistency were demonstrated in Table 4. Cronbach's alpha for the frequency and degree score of the subscale ocular symptoms, impact on daily life, and summary score range from 0.81 to 0.92. The two-week test-retest reliability was evaluated in 90 DED participants. The ICC ranged from 0.80 to 0.92, indicating excellent reproducibility.
Convergent Validity: Table 6 shows the correlation matrix between the QOL assessed by the subscale Impact on Daily Life of the DEQS-Th and scores from EQ-5D items, depression item of DEQS-Th significantly related to anxiety/depression items of EQ-5D, higher than other dimensions. The items of eye functions such as opening eyes, blurred vision, and sensitivity to bright light were related more to mobility, self-care, and usual activity of the EQ-5D. The items of QOL that were related to function such as reading, watching, and studying were, as expected, significantly related to the physical function domain of EQ-5D rather than the anxiety/depression domain. Items "Feeling distracted" and "Not feeling like going out" were related to both physical and anxiety/depression as they were involved in concentration. All significant correlations indicate convergent validity.
Clinical validity and responsiveness. The responsiveness was evaluated in ten patients receiving diquafosol treatment. At four weeks after treatment, the symptom scores of the DEQS-Th and CFS were significantly improved and the SRM were 0.816 and 1.061, respectively (Table 7).

Accuracy for DED screening
In predicting DED against the gold standard, we used the AUC as the criterion to compare the following set of items. The scale provided AUCs of 0.897 (p<0.001, 95%CI = 0.831 to 0.943) denoting good accuracy performance [32] (Fig 1A). The DEQS-Th yielded a sensitivity of 90.00 and specificity of 76.67% for the cut-off score � 18.33, based on Youden's index [33] (S1 Table). The AUCs of the SF DEQS-Th was 0.857 (p<0.001, 95% CI 0.785-0.912) and the optimal cut-off value was � 3, which yielded a sensitivity of 93.0% and specificity of 63.3% (Fig 1B, S2 Table).

Discussion
This study demonstrates the reliability and validity of the DEQS-Th questionnaire in dry eye patients. Our preliminary study found that the DEQS-Th has good internal consistency when  [14].
In addition, the DEQS-Th questionnaire has been shown to correlate well with the OSDI, which is a current gold standard. The OSDI is one of the most frequently used tools in DED assessment and has good psychometric properties in the assessment of subjective dry eye symptoms and their effects on visual-related activities within the previous week [25]. This study demonstrated that the DEQS-Th questionnaire has a criterion (concurrent) validity with the OSDI, consistent with a related study by Inomata et al. that demonstrated a strong correlation between the DEQS and the Japanese version of OSDI (J-OSDI) scores. They found that the J-OSDI scores tended to be higher than the DEQS (31.6 vs. 27.6) which was in accordance with our study [34]. Chronic DED can have multi-faceted effects on a patient's health including personality [35] and psychosomatic symptoms [7,36]. A previous study found that OSDI scores significantly correlated with the DEQS, anxiety, depression, and stress scores. Moreover, the severity of DED symptoms impacted more on the depressive symptoms [36]. Recently, a large-scale study using the mobile application suggests that depressive symptoms are more common in individuals with more severe dry eye symptoms [7]. The original DEQS questionnaire has been reported to correlate well with the mental components of the NEI VFQ-25 [14]. In this study, the QOL assessed by the subscale Impact on Daily Life of the DEQS-Th demonstrated convergent validity with the EQ-5D-5L. It is noted that all impact on QOL items is significantly related to the self-care and usual activities of the EQ-5D-5L, while most items are related to anxiety/depression indicating that DED influenced both the function and mental health of each affected individual. Nevertheless, DEQS-Th scores did not correlate with clinical signs of dry eye. This finding agrees with previous studies regarding the discordance between symptoms and signs of DED [11,12].  The discriminant validity of the DEQS-Th was verified from the finding that all DEQS-Th scores were significantly higher in the DED than those of the control groups. Our findings are in accordance with Sakane's study even though the average scores of subjects with DED and non-DED (33.7 vs. 6.0) were lower than those in our study [14]. The reasons may be due to the difference in the study population. Besides, both convergent and discriminant validity are evidence of the construct validity of the DEQS-Th questionnaire.
This study also examined the effect of treatment by using the DEQS-Th. We found that the symptom scores and CSF significantly improved after four weeks of diquafosol treatment. Although other parameters improved after receiving diquafosol, they did not reach statistical significance. Our results comply with a previous study using the DEQS questionnaire to evaluate the effects of diquafosol in DED [37]. They found that diquafosol improved both symptoms and signs in DED patients. Compared to Sakane's study, the DEQS scores and clinical signs (TBUT and fluorescein staining) significantly improved after treatment with a punctal plug [14]. The different results may be because the effects of topical medication like diquafosol may take more time than performing a lacrimal punctal occlusion. With a greater number of the study samples, diquafosol might have significantly changed the DEQS-Th scores and TBUT. Nevertheless, our findings suggest that DEQS-Th was useful in assessing the changes in DED symptoms and the therapeutic effect.
In predicting performance, DEQS-Th is shown to have good accuracy for detecting DED compared to the OSDI (AUC = 0.897 and 0.744 for DEQS and OSDI, respectively) [38]. This study also demonstrated the cut-off score of the DEQS-Th of � 18.33 for screening DED. Practically, a cut-off score of 18 can be applied even though the values of sensitivity and specificity might be slightly changed. This cut-off value is higher than the value of > 15 which was previously proposed by Ishikawa [39]. Ishikawa's study was conducted among 333 soldiers (mostly males), while most of the subjects in our study were relatively older females with more severe dry eye symptoms. The different cut-off values might be due to the variation of the patient demographics such as sex, age, and ethnicity. In addition, this study also provided the cut-off score of the SF DEQS-Th by using the subscale ocular symptoms for DED screening and the value of � 3 was the optimal criterion. The SF DEQS-Th is simple and can, further, be widely used in screening individuals with suspected DED. Thus, the burden for the physicians in reallife practice can be lowered. However, caution should be applied to diagnose DED based on symptoms only because the discrepancy between symptoms and signs from asymptomatic patients often occurs [12]. Therefore, it is important to use both the questionnaire and clinical examination for a holistic assessment of DED.
The strength of this study is a comprehensive assessment of the DEQS-Th, providing robust evidence in terms of its psychometric properties and performance prediction for detecting DED. Some limitations need to be mentioned. First, the study was conducted in a university hospital, tertiary care setting with a relatively high prevalence, compared to that of the general population with most patients experiencing a more severe degree of DED. Second, other factors such as medication, depression, anxiety, and environmental effects were not accounted for. This may have affected the results. Last, the sample size for testing responsiveness was small.

Conclusions
The DEQS-Th is valid and reliable for evaluating both dry eye symptoms and their impact on a patient's QOL. It demonstrates psychometric properties that can be useful for primary evaluation and monitoring of DED in clinical practice and research. This study also provides the cut-off score of the DEQS-Th for screening individuals with suspected DED, thus preventing morbidity from untreated disease.
Supporting information S1